Tricyclic 2-pyrimidone compounds useful as HIV reverse transcriptase inhibitors

ABSTRACT

The present invention relates to tricyclic 2-pyrimidone compounds of formula (I):  
                 
 
     or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

[0001] This application claims benefit to provisional application U.S.Serial No. 60/349,641 filed Jan. 18, 2002. The entire teachings of thereferenced application are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates generally to tricyclic pyrimidonecompounds which are useful as inhibitors of HIV reverse transcriptase,pharmaceutical compositions and diagnostic kits comprising the same,methods of using the same for treating viral infection or as assaystandards or reagents, and intermediates and processes for making suchtricyclic compounds.

BACKGROUND OF THE INVENTION

[0003] Two distinct retroviruses, human immunodeficiency virus (HIV)type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to theimmunosuppressive disease, acquired immunodeficiency syndrome (AIDS).HIV seropositive individuals are initially asymptomatic but typicallydevelop AIDS related complex (ARC) followed by AIDS. Affectedindividuals exhibit severe immunosuppression which predisposes them todebilitating and ultimately fatal opportunistic infections.

[0004] The disease AIDS is the consequence of HIV-1 or HIV-2 virusfollowing its complex viral life cycle. The virion life cycle involvesthe virion attaching itself to the host human T-4 lymphocyte immune cellthrough the binding of a glycoprotein on the surface of the virion'sprotective coat with the CD4 glycoprotein on the lymphocyte cell. Onceattached, the virion sheds its glycoprotein coat, penetrates into themembrane of the host cell, and uncoats its RNA. The virion enzyme,reverse transcriptase, directs the process of transcribing the RNA intosingle-stranded DNA. The viral RNA is degraded and a second DNA strandis created. The now double-stranded DNA is integrated into the humancell's genes and those genes are used for virus reproduction.

[0005] RNA polymerase transcribes the integrated viral DNA into viralmRNA. The viral RNA is translated into the precursor gag-pol fusionpolyprotein. The polyprotein is then cleaved by the HIV protease enzymeto yield the mature viral proteins. Thus, HIV protease is responsiblefor regulating a cascade of cleavage events that lead to the virusparticle's maturing into a virus that is capable of full infectivity.

[0006] The typical human immune system response, killing the invadingvirion, is taxed because the virus infects and kills the immune system'sT cells. In addition, viral reverse transcriptase, the enzyme used inmaking a new virion particle, is not very specific, and causestranscription mistakes that result in continually changed glycoproteinson the surface of the viral protective coat. This lack of specificitydecreases the immune system's effectiveness because antibodiesspecifically produced against one glycoprotein may be useless againstanother, hence reducing the number of antibodies available to fight thevirus. The virus continues to reproduce while the immune response systemcontinues to weaken. In most cases, without therapeutic intervention,HIV causes the host's immune,system to be debilitated, allowingopportunistic infections to set in. Without the administration ofantiviral agents, immunomodulators, or both, death may result.

[0007] There are at least three critical points in the HIV life cyclewhich have been identified as possible targets for antiviral drugs: (1)the initial attachment of the virion to the T-4 lymphocyte or macrophagesite, (2) the transcription of viral RNA to viral DNA (reversetranscriptase, RT), and (3) the processing of gag-pol protein by HIVprotease.

[0008] Inhibition of the virus at the second critical point, the viralRNA to viral DNA transcription process, has provided a number of thecurrent therapies used in treating AIDS. This transcription must occurfor the virion to reproduce because the virion's genes are encoded inRNA and the host cell transcribes only DNA. By introducing drugs thatblock the reverse transcriptase from completing the formation of viralDNA, HIV-1 replication can be stopped.

[0009] A number of compounds that interfere with viral replication havebeen developed to treat AIDS. For example, nucleoside analogs, such as

[0010] 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxythymidinene (d4T),

[0011] 2′,3′-dideoxyinosine (ddI), and

[0012] 2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to berelatively effective in certain cases in halting HIV replication at thereverse transcriptase (RT) stage.

[0013] An active area of research is in the discovery of non-nucleosideHIV reverse transcriptase inhibitors (NNRTIs). As an example, it hasbeen found that certain benzoxazinones and quinazolinones are active inthe inhibition of HIV reverse transcriptase, the prevention or treatmentof infection by HIV and the treatment of AIDS.

[0014] U.S. Pat. No. 5,874,430 describes benzoxazinone non-nucleosidereverse transcriptase inhibitors for the treatment of HIV. U.S. Pat. No.5,519,021 describe non-nucleoside reverse transcriptase inhibitors whichare benzoxazinones of the formula:

[0015] wherein X is a halogen, Z may be O.

[0016] EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptaseinhibitors which are quinazolinones of the formula (A):

[0017] wherein G is a variety of groups, R³ and R⁴ may be H, Z may be O,R² may be unsubstituted alkyl, unsubstituted alkenyl, unsubstitutedalkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, andoptionally substituted aryl, and R¹ may be a variety of groups includingsubstituted alkyl.

[0018] WO 95/12583 also describes HIV reverse transcriptase inhibitorsof formula A. In this publication, G is a variety of groups, R³ and R⁴may be H, Z may be O, R² is substituted alkenyl or substituted alkynyl,and R¹ is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273illustrates the asymmetric synthesis of one of the compounds of WO95/12583,(S)-(−)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethynyl)-2(1H)-quinazolinone.

[0019] Synthetic procedures for making quinazolinones like thosedescribed above are detailed in the following references: Houpis et al.,Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al., J. Med. Chem. 1994,37, 2437-2444; and, Huffman et al., J. Org. Chem. 1995, 60, 1590-1594.

[0020] DE 4,320,347 illustrates quinazolinones of the formula:

[0021] wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring.Compounds of this sort are not considered to be part of the presentinvention.

[0022] WO 01/29037 describes HIV reverse transcriptase inhibitors of theformula

[0023] wherein the A ring is a heteroaryl ring containing one or twonitrogen atoms.

[0024] Even with the current success of reverse transcriptaseinhibitors, it has been found that HIV patients can become resistant toa given inhibitor. Thus, there is an important need to developadditional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

[0025] Accordingly, the present invention provides novel reversetranscriptase inhibitors.

[0026] The present invention provides a novel method for treating HIVinfection which comprises administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention, including a pharmaceuticallyacceptable salt form thereof.

[0027] The present invention provides a novel method for treating HIVinfection which comprises administering to a host in need thereof atherapeutically effective combination of (a) one of the compounds of thepresent invention and (b) one or more compounds selected from the groupconsisting of HIV reverse transcriptase inhibitors and HIV proteaseinhibitors.

[0028] The present invention provides pharmaceutical compositions withreverse transcriptase inhibiting activity comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt form thereof.

[0029] The present invention provides novel tricyclic pyrimidonecompounds for use in therapy.

[0030] The present invention provides the use of novel tricyclicpyrimidone compounds for the manufacture of a medicament for thetreatment of HIV infection.

[0031] These and other aspects of the invention, which will becomeapparent during the following detailed description, have been achievedby the inventors' discovery that compounds of formula (I):

[0032] wherein ring A, R¹, R², R⁸, A, W, X, Y, and Z are defined below,including any stereoisomeric form, mixtures of stereoisomeric forms,complexes, prodrug forms or pharmaceutically acceptable salt formsthereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF EMBODIMENTS

[0033] [1] Thus, in an Embodiment, the Present Invention Provides aNovel Compound of Formula (I):

[0034] or a stereoisomeric form or mixture of stereoisomeric forms or apharmaceutically acceptable salt form thereof, wherein:

[0035] A is a ring selected from:

[0036] P is O or S;

[0037] Q is O or NH;

[0038] R^(a) is selected from H, CN, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, OH, C₁₋₄ alkyl-O—, C₁₋₄ alkyl-NH−, and NH₂;

[0039] R^(b) is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, and C₁₋₄alkynyl;

[0040] W is N or CR³;

[0041] X is N or CR^(3a);

[0042] Y is N or CR^(3b);

[0043] Z is N or CR^(3c);

[0044] provided that if two of W, X, Y, and Z are N, then the remainingare other than N;

[0045] R¹ is selected from the group cyclopropyl, hydroxymethyl, CN, andC₁₋₄ alkyl substituted with 0-9 halogen;

[0046] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₆ alkyl substituted with 0-2 R⁴, C₂₋₆ haloalkyl, C₂₋₅ alkenylsubstituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆cycloalkyl substituted with 0-2 R^(3d), phenyl substituted with 0-2R^(3d), and 3-6 membered heterocyclic system containing 1-3 heteroatomsselected from the group O, N, and S, substituted with 0-2 R^(3d);

[0047] R³ is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy,OCF₃, CF₃, F, Cl, Br, I, —(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—(CH₂)_(t)NHC(O)R⁷, —(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R₁₀, —S—C₁₋₄alkyl,—S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S;

[0048] R^(3a) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, CF₃, F, Cl, Br, I, —(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN,—C(O)R⁶, —(CH₂)_(t)NHC(O)R⁷, —(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰,—S—C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6membered heteroaromatic ring containing 1-4 heteroatoms selected fromthe group O, N, and S;

[0049] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0050] R^(3b) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0051] alternatively, R^(3a) and R^(3b) together form —OCH₂O—;

[0052] R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0053] alternatively, R^(3b) and R^(3c) together form —OCH₂O—;

[0054] R^(3d), at each occurrence, is independently selected from thegroup H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a),—NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and—SO₂NR⁵R^(5a);

[0055] R^(3e), at each occurrence, is independently selected from thegroup H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a),—NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and—SO₂NR⁵R^(5a);

[0056] R^(3f),at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C¹⁻⁴ alkyl, CN, —OH, —O—R¹¹, OCF₃, —O(CO)—R¹³,—OS (O)₂C₁₋₄alkyl, —NR¹²R^(12a), —C(O)R¹³, —NHC(O)R¹³, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, —NHSO₂R¹⁰, and —SO₂NR¹²R^(12a);

[0057] R⁴ is selected from the group H, F, Cl, Br, I, C₁₋₆ alkylsubstituted with 0-2 R^(3e), C₃₋₁₀ carbocycle substituted with 0-2R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-10 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-2 R^(3e);

[0058] R⁵ and R^(5a) are independently selected from the group H andC₁₋₄ alkyl;

[0059] alternatively, R⁵ and R^(5a), together with the nitrogen to whichthey are attached, combine to form a 5-6 membered ring containing 0-1 Oor N atoms;

[0060] R⁶ is selected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, andNR⁵R^(5a);

[0061] R⁷ is selected from the group H, C₁₋₃ alkyl and C₁₋₃ alkoxy;

[0062] R⁸ is selected from the group H, (C₁₋₆ alkyl)carbonyl, C₁₋₆alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)oxycarbonyl,(C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄ alkyl)carbonyloxy(C₁₋₄alkoxy)carbonyl, C₆₋₁₀ arylcarbonyloxy(C₁₋₄ alkoxy)carbonyl, C₁₋₆alkylaminocarbonyl, phenylaminocarbonyl, phenyl(C₁₋₄ alkoxy)carbonyl,and NR⁵R^(5a)(C₁₋₆ alkyl)carbonyl;

[0063] R⁹ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl,(C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy,(C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ arylcarbonyloxy(C₁₋₄alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl,phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆ alkyl)carbonyl;

[0064] R¹⁰ is selected from the group C₁₋₄ alkyl and phenyl;

[0065] R¹¹ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylsubstituted with C₃₋₆cycloalkyl substituted with 0-2 R^(3e), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocycle substituted with 0-2 R^(3e);

[0066] R¹² and R^(12a) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkyl substituted with C₃₋₆cycloalkyl substituted with 0-2 R^(3e),and C₃₋₆ carbocycle substituted with 0-2 R^(3e);

[0067] alternatively, R¹² and R^(12a) can join to form 4-7 memberedheterocyclic ring;

[0068] R¹³ is selected from the group H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —O—C₂₋₆ alkenyl, —O—C₂₋₆alkynyl, NR¹²R^(12a), C₃₋₆carbocycle, and —O—C₃₋₆carbocycle; and

[0069] t is selected from 0 and 1.

[0070] [2] In Another Embodiment, the Present Invention ProvidesCompounds of Formula (I), Wherein:

[0071] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₅ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(3d), and phenyl substituted with 0-2 R^(3d), and 3-6membered heterocyclic system containing 1-3 heteroatoms selected fromthe group O, N, and S, substituted with 0-2 R^(3d), wherein theheterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl,4-isoxazolyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and1,3-dioxanyl;

[0072] R³ and R^(3a), at each occurrence, are independently selectedfrom the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a),NO₂, —CN, C(O)R⁶, NHC(O)R⁷, NHC(O)NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S;

[0073] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0074] R^(3b) and R^(3c), at each occurrence, are independently selectedfrom the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a),NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

[0075] alternatively, R^(3a) and R^(3b) together form —OCH₂O—;

[0076] R⁴ is selected from the group H, Cl, F, C₁₋₄ alkyl substitutedwith 0-2 R^(3e), C₃₋₆ carbocycle substituted with 0-2 R^(3e), phenylsubstituted with 0-5 R^(3e), and a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-2 R^(3e);

[0077] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0078] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a); and

[0079] R⁷ is selected from the group CH₃, C₂H₅, CH(CH₃)₂, OCH₃, OC₂H₅,and OCH(CH₃)₂.

[0080] [3] In Another Embodiment, the Present Invention ProvidesCompounds of Formula (I), Wherein:

[0081] P is O;

[0082] Ring A is:

[0083] R^(a), at each occurrence, is selected from H, C₁₋₄ alkyl, C₁₋₄alkyl-NH—, NH₂;

[0084] R^(c) is selected from H and methyl;

[0085] W is CR³;

[0086] X is CR^(3a);

[0087] Y is CR^(3b);

[0088] Z is CR^(3c);

[0089] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₃ alkyl substituted with 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2R⁴, C₂₋₃ alkynyl substituted with 0-1 R⁴, and C₃₋₆ cycloalkylsubstituted with 0-2 R^(3d);

[0090] R³, R^(3a), R^(3b), and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F,Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

[0091] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0092] R^(3e), at each occurrence, is independently selected from thegroup H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, —NR⁵R^(5a), —C(O)R⁶,and —SO₂NR⁵R^(5a);

[0093] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —O(CO)—R¹³, —SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, and —NR¹²R^(12a);

[0094] R⁴ is selected from the group H, Cl, F, C₁₋₄ alkyl substitutedwith 0-1 R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenylsubstituted with 0-2 R^(3e), and a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-1 R^(3e), wherein the heterocyclic system is selectedfrom 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl,pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl;

[0095] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0096] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a);

[0097] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅;

[0098] R⁸ is H;

[0099] R⁹ is H, methyl, ethyl, propyl, and i-propyl;

[0100] R¹¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, and C₃₋₆ carbocycle substituted with 0-2 R^(3e)wherein the C₃₋₆ carbocycle is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and phenyl; and

[0101] R¹² and R^(12a) are independently selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocyclesubstituted with 0-2 R^(3e) wherein the C₃₋₆ carbocycle is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl.

[0102] [4] In Another Embodiment, the Present Invention ProvidesCompounds of Formula (I), Wherein:

[0103] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₃ alkyl substituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴,and C₂₋₃ alkynyl substituted with 1 R⁴;

[0104] R³, R^(3a), R^(3b), and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F,Cl, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

[0105] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0106] R^(3e), at each occurrence, is independently selected from thegroup CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a);

[0107] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, —OH, CN, —O—R¹¹, —O(CO)—R¹³, and—NR¹²R^(12a), —SR¹¹, —S(O)R¹¹, S(O)₂R¹¹, and —OS(O)₂methyl;

[0108] R⁴ is selected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropylsubstituted with 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1R^(3e), cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with0-2 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl;

[0109] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0110] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a);

[0111] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and

[0112] R⁹ is selected from H and methyl.

[0113] [5] In Another Embodiment, the Present Invention ProvidesCompounds of Formula (I), Wherein:

[0114] R² is selected from the group methyl substituted with 0-2 R^(3f),methyl substituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-2 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴, 2-propynylsubstituted with 0-2 R⁴, and cyclopropyl substituted with 0-1 R^(3d);

[0115] R^(3e), at each occurrence, is independently selected from thegroup CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a);

[0116] R⁴ is selected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropylsubstituted with 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1R^(3e), cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with0-2 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl;

[0117] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0118] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a);

[0119] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅;

[0120] R⁸ is H.

[0121] [6] In Another Embodiment, the Present Invention ProvidesCompounds of Formula (I), Wherein:

[0122] R¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,cyclopropyl, CF₃, CF₂CH₃, CN, and hydroxymethyl;

[0123] R² is selected from the group methyl substituted with 0-2 R^(3f),methyl substituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-1 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴;

[0124] R³, R^(3b), and R^(3c) are H;

[0125] R^(3e) is CH₃;

[0126] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —NR¹²R^(12a);

[0127] R⁴ is selected from the group H, cyclopropyl substituted with 0-1R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl;

[0128] R¹² and R^(12a) are independently selected from H, methyl, ethyl,propyl, and i-propyl, and C₃₋₆ carbocycle substituted with 0-2 R^(3e)wherein the C₃₋₆ carbocycle is selected from cyclopropyl.

[0129] [7] In Another Embodiment, the Present Invention ProvidesCompounds of Formula (I), Wherein:

[0130] ring A is O

[0131] R^(a) is H, methyl, ethyl, propyl, and i-propyl;

[0132] R¹ is CF₃;

[0133] R² is selected from methyl substituted with 0-1 R^(3f), ethyl,propyl, i-propyl, and butyl;

[0134] W is CH;

[0135] X is CR^(3a);

[0136] Y is CH;

[0137] Z is CH;

[0138] R^(3a) is selected from H, F, Cl, Br, and CN;

[0139] R^(3f) is —O—R¹¹;

[0140] R⁸ is H; and

[0141] R¹¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,s-butyl, i-butyl, and t-butyl.

[0142] [8] In Another Embodiment, Compounds of the Present Invention areThose Compounds Wherein the Compound is of Formula (Ic):

[0143] [8] In another embodiment, compounds of the present inventioninclude compounds of formula (I) wherein the compound of formula (I) isselected from is selected from:

[0144]10-Butyl-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0145]10-Butyl-8-cyano-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0146]8-Chloro-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0147]8-Cyano-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0148]10-Butyl-8-chloro-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0149]8-Chloro-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0150]8-Cyano-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0151]8-Chloro-10-(2-cyclopropylethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;

[0152]8-Cyano-10-(2-cyclopropylethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;and

[0153]10-(4-Bromobenzyl)-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b] quinolin-4(3H)-one.

[0154] The present invention also provides a novel pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt form thereof

[0155] The compositions and methods of use comprising the compounds ofthe present invention include compositions and methods of use comprisingthe compounds of the present invention and stereoisomeric forms thereof,mixtures of stereoisomeric forms thereof, complexes thereof, crystallineforms thereof, prodrug forms thereof and pharmaceutically acceptablesalt forms thereof

[0156] In another embodiment, the present invention provides a novelmethod for treating HIV infection which comprises administering to ahost in need of such treatment a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt formthereof

[0157] In another embodiment, the present invention provides a novelmethod of treating HIV infection which comprises administering, incombination, to a host in need thereof a therapeutically effectiveamount of:

[0158] (a) a compound of formula (I); and

[0159] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors and HIV protease inhibitors.

[0160] In another embodiment, the present invention provides a novelmethod of treating HIV infection which comprises administering, incombination, to a host in need thereof a therapeutically effectiveamount of:

[0161] (a) a compound of formula (I); and

[0162] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors, HIV protease inhibitors, CCR-5inhibitors, and fusion inhibitors.

[0163] In another embodiment reverse transcriptase inhibitors useful inthe above method of treating HIV infection are selected from the groupAZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893,trovirdine, MKC-442, HBY 097, HBY1293, GW867, ACT, UC-781, UC-782,RD4-2025, MEN 10979, AG1549 (S1153), TMC-120, TMC-125, Calanolide A, andPMPA. Protease inhibitors useful in the above method of treating HIVinfection are selected from the group saquinavir, ritonavir, indinavir,amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272,LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392,U-140690, ABT-378, DMP-450, AG-1776, VX-175, MK-944, and VX-478, theCCR-5 inhibitor is selected from TAK-779 (Takeda), SC-351125 (SCH-C,Schering) and SCH-D (Schering), and the fusion inhibitor is selectedfrom T-20 amd T1249.

[0164] In another embodiment, the reverse transcriptase inhibitor isselected from the group AZT, efavirenz, and 3TC and the proteaseinhibitor is selected from the group saquinavir, ritonavir, nelfinavir,and indinavir.

[0165] In another embodiment, the reverse transcriptase inhibitor isAZT.

[0166] In another embodiment, the protease inhibitor is indinavir.

[0167] In another embodiment, the present invention provides apharmaceutical kit useful for the treatment of HIV infection, whichcomprises a therapeutically effective amount of:

[0168] (a) a compound of formula (I); and,

[0169] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors and HIV protease inhibitors, in oneor more sterile containers.

[0170] In another embodiment, the present invention provides noveltricyclic 2-pyrimidone compounds for use in therapy.

[0171] In another embodiment, the present invention provides the use ofnovel tricyclic 2-pyrimidone compounds for the manufacture of amedicament for the treatment of HIV infection.

[0172] In another embodiment, the present invention

[0173] provides that Ring A is

[0174] In another embodiment, the present invention provides that Ring Ais

[0175] In another embodiment, the present invention provides that R¹ isselected from CF₃, CF₂CH₃, and CHF₂.

[0176] In another embodiment, the present invention provides that R¹ isCF₃.

[0177] In another embodiment, the present invention provides that R¹ isselected from the group CF₃, C₂F₅, CF₂CH₃, CHF₂, CH₂F and cyclopropyl.

[0178] In another embodiment, the present invention provides that R¹ ismethyl substituted with 0-3 R^(3f), and C₂₋₅ alkyl substituted with 0-2R⁴, wherein the _(C2-)5 alkyl is selected from ethyl, propyl, i-propyland butyl.

[0179] In another embodiment, the present invention provides that R¹ isCN and hydroxymethyl.

[0180] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₅ alkylsubstituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2R^(3d), and phenyl substituted with 0-2 R^(3d), and 3-6 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-2 R^(3d), wherein the heterocyclicsystem is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl,3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl,2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.

[0181] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₃ alkylsubstituted with 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2 R⁴, C₂₋₃alkynyl substituted with 0-1 R⁴, and C₃₋₆ cycloalkyl substituted with0-2 R^(3d).

[0182] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₃ alkylsubstituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴, and C₂₋₃alkynyl substituted with 1 R⁴.

[0183] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-2 R^(3f), methylsubstituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-2 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴, 2-propynylsubstituted with 0-2 R⁴, and cyclopropyl substituted with 0-1 R^(3d).

[0184] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-2 R^(3f), methylsubstituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-1 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴.

[0185] In another embodiment, R² is selected from the group methylsubstituted with 0-2 R^(3f), methyl substituted with 0-2 R⁴, and ethylsubstituted with 0-2 R⁴.

[0186] In another embodiment, the present invention provides thatR^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —O(CO)—R¹³, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —NR¹²R^(12a).

[0187] In another embodiment, the present invention provides thatR^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, C₁₋₄ alkyl, —OH, CN —O—R¹¹, —O(CO)—R¹³, and —NR¹²R^(12a),—SR¹¹, —S(O)R¹¹, S(O)₂R¹¹, and —OS(O)₂methyl.

[0188] In another embodiment, the present invention provides thatR^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,and —NR¹²R^(12a).

[0189] In another embodiment, the present invention provides thatR^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, and —O—R¹¹.

[0190] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, C₁₋₄ alkyl substituted with 0-2R^(3e), C₃₋₆ carbocycle substituted with 0-2 R^(3e), phenyl substitutedwith 0-5 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-2R^(3e).

[0191] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, C₁₋₄ alkyl substituted with 0-1R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substitutedwith 0-2 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.

[0192] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropyl substitutedwith 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1 R^(3e),cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with 0-2R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl.

[0193] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropyl substitutedwith 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1 R^(3e),cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with 0-2R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl.

[0194] In another embodiment, the present invention provides that R⁸ isH.

[0195] In another embodiment, the present invention provides that R⁹ isselected from H, methyl, ethyl, propyl, and i-propyl.

[0196] In another embodiment, the present invention provides that R⁹ isH.

[0197] In another embodiment, the present invention provides that R¹¹isselected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,and C₃₋₆ carbocycle substituted with 0-2 R^(3e) wherein the C₃₋₆carbocycle is selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and phenyl.

[0198] In another embodiment, the present invention provides that R¹²and R^(12a) are independently selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocycle substituted with0-2 R^(3e)wherein the C₃₋₆ carbocycle is selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and phenyl.

[0199] In another embodiment, the present invention provides that W isCR³; X is CR^(3a); Y is CR^(3b); and Z is CR^(3c).

[0200] In another embodiment, the present invention provides that W isCH; X is CR^(3a); Y is CH; and Z is CH.

[0201] In another embodiment, the present invention provides that W isCR³; X is CR^(3a); Y is CR^(3b); and Z is N or CR^(3c).

[0202] In another embodiment, the present invention provides that W isCR³; X is CR^(3a); Y is N or CR^(3b); and Z is N or CR^(3c).

[0203] In another embodiment, the present invention provides that W isCR³; X is N or CR^(3a); Y is CR^(3b); and Z is N or CR^(3c).

[0204] In another embodiment, the present invention provides that W is Nor CR³; X is CR^(3a); Y is CR^(3b); and Z is N or CR^(3c).

[0205] The invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention also encompasses all combinations of aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment are meant to be combined withany and all other elements from any of the embodiments to describeadditional embodiments.

DEFINITIONS

[0206] It will be appreciated that the compounds of the presentinvention contain an asymmetrically substituted carbon atom, and may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated. All tautomers of shown ordescribed compounds are also considered to be part of the presentinvention.

[0207] As used herein, the term “tricyclic 2-pyrimidones” is intended toinclude the compounds 5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-onewhich are represented by the compounds of Formula I.

[0208] The present invention is intended to include all isotopes ofatoms occurring on the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0209] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom or ring is replaced with aselection from the indicated group, provided that the atom's, or thering atom's, normal valency is not exceeded, and that the substitutionresults in a stable compound. When a substituent is keto (i.e., =O),then 2 hydrogens on the atom are replaced. When a ring system (e.g.,carbocyclic or heterocyclic) is said to be substituted with a carbonylgroup or a double bond, it is intended that the carbonyl group or doublebond be part (i.e., within) of the ring.

[0210] When any variable (e.g., R^(c)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁴, then saidgroup may optionally be substituted with up to two R⁴ groups and R⁴ ateach occurrence is selected independently from the definition of R⁴.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

[0211] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0212] As used herein, the following terms and expressions have theindicated meanings.

[0213] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. By way of illustration, the term“C₁₋₁₀, alkyl” or “C₁-C₁₀ alkyl” is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. “C₁₋₄ alkyl” is intended toinclude C₁, C₂, C₃, and C₄ alkyl groups. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).Examples of haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” is intended to include hydrocarbon chains of either astraight or branched configuration and one or more unsaturatedcarbon-carbon bonds which may occur in any stable point along the chain,such as ethenyl, propenyl and the like. C₂₋₁₀ alkenyl, is intended toinclude C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkenyl groups.“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more triple carbon-carbon bondswhich may occur in any stable point along the chain, such as ethynyl,propynyl and the like. C₂₋₁₀ alkynyl, is intended to include C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkynyl groups.

[0214] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo. “Counterion” is used to represent a small, negativelycharged species such as chloride, bromide, hydroxide, acetate, sulfateand the like.

[0215] As used herein, “aryl” or “aromatic residue” is intended to meanan aromatic moiety containing the specified number of carbon atoms, suchas phenyl or naphthyl. As used herein, “carbocycle” or “carbocyclicresidue” is intended to mean any stable 3, 4, 5, 6, or 7-memberedmonocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl.

[0216] As used herein, the term “heterocycle” or “heterocyclic system”is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicor 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturatedpartially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized. Anoxo group may be a substituent on a nitrogen heteroatom to form anN-oxide. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. It is preferred that the total number of S and O atoms in theheterocycle is not more than 1. As used herein, the term “aromaticheterocyclic system” is intended to mean a stable 5, 6, or 7-memberedmonocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclicaromatic ring which consists of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, O andS. It is preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 1.

[0217] Examples of heterocycles include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 1,3-dioxolanyl, 1,3-dioxanyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

[0218] As used herein, “HIV reverse transcriptase inhibitor” is intendedto refer to both nucleoside and non-nucleoside inhibitors of HIV reversetranscriptase (RT). Examples of nucleoside RT inhibitors include, butare not limited to, AZT, ddC, ddI, d4T, PMPA, and 3TC. Examples ofnon-nucleoside RT inhibitors include, but are no limited to, delavirdine(Pharmacia and Upjohn U90152S), efavirenz (DuPont), nevirapine(Boehringer Ingelheim), trovirdine (Lilly), MKC-442 (Triangle), HBY 097(Hoechst), HBY1293 (Hoechst), GW867 (Glaxo Wellcome), ACT (KoreanResearch Institute), UC-781 (Rega Institute), UC-782 (Rega Institute),RD4-2025 (Tosoh Co. Ltd.), MEN 10979 (Menarini Farmaceutici) AG1549(S1153; Agouron), TMC-120, TMC-125, and Calanolide A.

[0219] As used herein, “HIV protease inhibitor” is intended to refer tocompounds that inhibit HIV protease. Examples include, but are notlimited, saquinavir (Roche, Ro3-8959), ritonavir (Abbott, ABT-538),indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome),nelfinavir (Agouron, AG-1343), palinavir (Boehringer Ingelheim),BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413(Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical),CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (ParkeDavis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690(Pharmacia and Upjohn), tipranavir (Pharmacia and Upjohn, U-140690),DMP-450 (DuPont), AG-1776, VX-175, MK-944, VX-478 and ABT-378.Additional examples include the cyclic protease inhibitors disclosed inWO93/07128, WO 94/19329, WO 94/22840, and PCT Application NumberUS96/03426.

[0220] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carbbxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[0221] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0222] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication commensurate with a reasonable benefit/risk ratio.

[0223] Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.Examples of prodrugs at R⁸ and at R⁹ are C₁₋₆ alkylcarbonyl, C₁₋₆alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl.

[0224] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. Only stable compounds are contemplated bythe present invention.

[0225] “Therapeutically effective amount” is intended to include anamount of a compound of the present invention alone or an amount of thecombination of compounds claimed or an amount of a compound of thepresent invention in combination with other active ingredients effectiveto inhibit HIV infection or treat the symptoms of HIV infection in ahost. The combination of compounds may be a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul. 22:27-55 (1984), occurs when the effect (in this case, inhibitionof HIV replication) of the compounds when administered in combination isgreater than the additive effect of the compounds when administeredalone as a single agent. In general, a synergistic effect is mostclearly demonstrated at suboptimal concentrations of the compounds.Synergy can be in terms of lower cytotoxicity, increased antiviraleffect, or some other beneficial effect of the combination compared withthe individual components.

[0226] As used herein, “treating” or “treatment” cover the treatment ofa disease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

[0227] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

SYNTHESIS

[0228] The compounds of Formula I can be prepared using the reactionsand techniques described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

[0229] Co-pending U.S. patent applications Ser. No. 09/691,249 filedOct. 18, 2000 and Ser. No. 09/908,995, filed Jul. 19, 2001, which arehereby incorporated by reference, describes the synthesis of tricycliccompounds.

[0230] Scheme 1 illustrates a method of preparing keto-anilines from anappropriately substituted 2-aminobenzoic acid (wherein R represents R³,R^(3a), R^(3b), and R^(3c)). The acid is converted to itsN-methoxy-N-methyl amide derivative which can then be displaced toobtain the R¹-substituted ketone. The keto-anilines are usefulintermediates for the presently claimed compounds.

[0231] Scheme 2 describes another method of preparing keto-anilines,this time from an appropriately substituted aniline. After iodinationand amine protection, a group such as trifluoromethyl can be introducedusing a strong base and ethyl trifluoroacetate. Deprotection providesthe keto-aniline. Additional means of preparing keto-anilines are knownto one of skill in the art, e.g, Houpis et al, Tetr. Lett. 1994, 35(37),6811-6814, the contents of which are hereby incorporated herein byreference.

[0232] Another method of making 2-trifluoroacetylanilines is shown inScheme 3. After forming the protected aniline, the amide is then reducedand the trifluoromethyl group added. Oxidation with an oxidant, such asMnO₂, provides the useful intermediate.

[0233] While the above schemes describe methods of preparing the benzoanalogs (i.e. wherein W, X, Y, and Z are all carbon), they can bemodified by one skilled in the art to prepare the heterocyclic varietieswherein W, X, Y, or Z are equal to nitrogen.

[0234] Scheme 4 illustrates specific steps for forming the aminoketoneIIIc. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃CF₂, andCF₃CF₂CF₂) is useful for making some of the presently claimed compounds.Pg is an amine protecting group as defined previously, for exampletrityl (triphenylmethyl). The protected or unprotectedaminobenzaldehyde, preferably protected, is treated with a perfluoralkyltrimethylsilane, preferably trifluoromethyl trimethylsilane, followed byfluoride anion, such as tetrabutylammonium fluoride. In the samefashion, CF₃CF₂TMS, CF₃CF₂CF₂TMS can also be used to prepare theappropriately substituted ketones. Other sources of fluoride anion suchas sodium fluoride, potassium fluoride, lithium fluoride, cesiumfluoride as well as oxyanionic species such as potassium tert-butoxide,sodium methoxide, sodium ethoxide and sodium trimethylsilanolate canalso be used. Aprotic solvents such as DMF and THF can be used,preferably THF. The amount of perfluoralkyl trimethylsilane used can befrom about 1 to about 3 equivalents with an equivalent amount offluoride anion or oxyanionic species. The reaction can be typicallycarried out at temperatures between about −20° C. to about 50° C., orabout −10 to about 10° C., or about 0° C.

[0235] Conversion of IIIb to IIIc can be achieved by using an oxidizingagent well known to one of skill in the art such as MnO₂, PDC, PCC,K₂Cr₂O₇, CrO₃, KMnO₄, BaMNO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant isMnO₂. Such conversion can be performed in an aprotic solvent like THF,DMF, dichloromethane dichloroethane, or tetrachloroethane, preferablydichloromethane.

[0236] In addition to the methods of obtaining keto-anilines describedin Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can alsobe used as shown in Scheme 5. This reaction is accomplished by using ananionic nucleophile of the group R^(1a). See Mack et al, J. HeterocyclicChem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41 (6),825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15 (1), 37-38;Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959,24, 1214-1219.

[0237] The stoichiometry of the isatoic anhydride reagent to nucleophileis about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g.,1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anionprecursor) is used to force the conversion and improve the isolatedyield. The temperature used is from −20 to +35° C., such as temperaturesbelow 0° C. being, or at −20° C. Reactions are run to about completionwith time dependent upon inter alia nucleophile, solvent, andtemperature. The nucleophilic addition is run in THF, for example, butany aprotic solvent would be suitable. Reaction with the activenucleophilic anion is the only criterion for exclusion of a solvent.

[0238] Patent Publications WO98/14436, WO98/45276, and WO01/29037describe other methods of preparing the appropriately substitutedanilines and are hereby incorporated by reference.

[0239] The resulting keto-anilines described in the above schemes can bemodified to the compounds of the present invention using the schemesdescribed in the examples.

[0240] One enantiomer of a compound of Formula I may display superioractivity compared with the other. Thus, both of the followingstereochemistries are considered to be a part of the present invention.

[0241] When required, separation of the racemic material can be achievedby HPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605.

[0242] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES

[0243] Abbreviations used in the Examples are defined as follows: “° C.”for degrees Celsius, “d” for doublet, “dd” for doublet of doublets, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “H” for hydrogen orhydrogens, “hr” for hour or hours, “m” for multiplet, “M” for molar,“min” for minute or minutes, “MHz” for megahertz, “MS” for massspectroscopy, “nmr” or “NMR” for nuclear magnetic resonancespectroscopy, “t” for triplet, “TLC” for thin layer chromatography,“ACN” for acetic anhydride, “CDI” for carbonyl diimidazole, “DIEA” fordiisopropylethylamine, “DIPEA” for diisopropylethylamine, “DMAP” fordimethylaminopyridine, “DME” for dimethoxyethane, “EDAC” for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “LAH” forlithium aluminium hydride, “TBAF” for tetrabutylammonium fluoride,“TBS-Cl” for t-butyldimethylsilyl chloride, and “TEA” for triethylamine.

[0244] All reactions were run under a nitrogen atmosphere at roomtemperature and most were not optimized. The reactions were followed byTLC. Reactions run over night were done so for adequate time. Reagentswere used as received. Dimethylformamide, tetrahydrofuran andacetonitrile were dried over molecular sieves. All other solvents werereagent grade. Ethanol and methanol were absolute and water wasdeionized. Melting points were determined in open capillary tubes on aMel-Temp apparatus and are uncorrected. Column chromatographies weredone on flash silica gel. Exceptions to any of the conditions above arenoted in the text. Ciral HPLC separations were done using chiral columnswhich gave the enantiomers in >99% EE.

[0245] The following methods are illustrated in the synthethic schemesthat follow the methods. While the schemes are described for specificcompounds, the same methods were employed to synthesize the othercompounds that are listed in the table of examples.

Example 1

[0246]

[0247] 6-Chloro-3-nitro-4-(trifluoromethyl)quinoline (2): Preparation ofMethazonic acid: To a stirred solution of NaOH (10.74 g, 179 mmol) inH₂O (60 mL) was added CH₃NO₂ dropwise maintaing the temperature between45-50° C. Once the addition was complete, the reaction was cooled to 0°C. and the pH was adjusted to 1 by the slow addition of conc. HCl withcare to keep the temperature below 10° C.

[0248] The solution of methazonic acid was poured into a stirred rtsolution of 2-amino-5-chloro-trifluoromethylacetophenone inH₂O-acetone-HCl (200-120-24 mL). After approximately 20 minutes a yellowprecipitate began to form. The reaction mixture was stirred overnight atrt and the precipitate (12.08 g) collected by filtration. The yellowsolid was treated with p-TsOH.H₂O in EtOH (100 mL) and heated to refluxfor 1 h. The reaction was cooled at rt and the solvent reduced in halfby rotary evaporation. The yellow crystalline solid was collected byfiltrated and washed with cold EtOH to afford 2 (9.41 g, 76%, twosteps). mp 107-110° C., (needles, EtOH). R_(f) 0.33 (5% Ethylacetate-hexane). ¹H NMR (d₆-DMSO, 300 MHz) δ9.53 (s, 1H), 8.38 (d, J=9.1Hz, 1H), 8.22 (m, 1H), 8.18 (dd, J=9.1, 2.2 Hz, 1H); ¹³C NMR (d₆-DMSO,75 MHz) δ147.54, 144.63, 136.42, 134.00, 132.94, 123.94, 122.11, 97.46,94.72, 83.79; ¹⁹F NMR (d₆-DMSO, 300 MHz) δ-56.46; IR (KBr) υ_(max) 1608,1543, 1495, 1376, 1362, 1300, 1289, 1259, 1252, 1214, 1174, 1164, 1147,1128, 1094, 848, 818, 664, 649 cm⁻¹.

[0249] Anal. Calcd for C₁₀H₄ClF₃N₂O₂: C, 43.42; H, 1.46; N, 10.13.Found: C, 43.47; H, 1.47; N, 9.90.

[0250] 6-Chloro-3-nitro-4-(trifluoromethyl)quinoline 1-oxide (3): Amixture of 2 (22.89 g, 83 mmol) and urea-hydrogen peroxide complex (15.6g, 166 mmol, 2 equiv) were suspended in CH₃CN (420 mL) and cooled to 0°C. Trifluoroacetic anhydride (24.5 mL, 174 mmol, 2.1 equiv) was addedslowly keeping the temperature below 7° C. The reaction was stirred at0° C. for 1 h then warmed to rt and stirred for an additional hour atwhich point the reaction was complete by TLC. The reaction mixture wasquenched by the addition of 250 mL of NaHSO₃ and then poured into 0.5 NHCl (600 mL). The aqueous phase was extracted with 3×150 mL of EtOAc.The combined organics were washed with brine, dried over MgSO₄, andconcentrated. Recrystallization of the resulting solid from EtOHafforded the desired product as a light tan crystalline solid (17.3 g,71%). mp 130° C. R_(f) 0.30 (10% Ethyl acetate-hexane). ¹H NMR (CDCl₃,300 MHz) δ8.73 (d, J=9.3 Hz, 1H), 8.54 (s, 1H), 8.26 (m, 1H), 7.88 (dd,J=2.0, 9.3 Hz, 1H); ¹⁹F NMR (CDCl₃, 300 MHz) δ-55.91; ¹³C NMR (CDCl₃, 75MHz) δ141.74, 139.21, 133.54, 128.90, 125.67, 125.61, 123.01, 122.12,119.37; IR (KBr) υ_(max) 3104, 1584, 1558, 1498, 1360, 1324, 1284, 1249,1178, 1160, 1137, 1128, 839 cm⁻¹.

[0251] Anal. Calcd for C₁₀H₄ClF₃N₂O₃: C, 41.05; H, 1.38; N, 9.57. Found:C, 41.02; H, 1.43; N, 9.48.

[0252] 2-Bromo-6-chloro-3-nitro-4-(trifluoromethyl)quinoline (4): Amixture of 3 (4.71 g, 16.1 mmol) and POBr₃ (9.23 g, 32.2 mmol) wereheated to 100° C. After 2 h, the reaction was cooled to rt andpartitioned between EtOAc and H₂O, adding ice when necessary. Themixture was stirred overnight to break up the solid materials. Et₂O (100mL) was added and the organic phase was removed. The remaining aqueousphase was extracted with EtOAc (3×100 mL). The combined organic phaseswere washed with brine, dried over MgSO₄ and concentrated to afford 5.5g (96%) of the desired product which was used without furtherpurification. An analytically pure sample was obtained byrecrystallization (EtOH) to provide a fluffy off-white solid, mp 120° C.R_(f) 0.61 (10% Ethyl acetate-hexane). ¹H NMR (CDCl₃, 300 MHz) δ8.16 (d,J=9.1 Hz, 1H), 8.16 (m, 1H), 7.92 (dd, J=2.2, 9.1 Hz, 1H); ¹⁹F NMR(CDCl₃, 300 MHz) δ-57.63; ¹³C NMR (CDCl₃, 75 MHz) δ146.50, 137.35,134.25, 131.88, 131.32, 124.45, 124.40, 122.44, 121.96, 118.76; IR (KBr)υ_(max) 1606, 1588, 1552, 1492, 1426, 1382, 1361, 1308, 1283, 1219,1180, 1169, 1157, 1134, 1097, 1023, 960, 846, 823, 792, 693, 661, 632cm⁻¹.

[0253] Anal. Calcd for C₁₀H₃BrClF₃N₂O₂: C, 33.79; H, 0.851; N, 7.88.Found: C, 33.60; H, 1.06; N, 7.49.

[0254] Alternatively, the above reaction can be run using the followingprocedure: POBr₃ (39.2 g, 137 mmol, 2 equiv) was added to a stirredsolution of 3 (20 g, 68 mmol) in dichloroethane (150 mL). The reactionwas heated to reflux for 8 h. After cooling to rt, the reaction wasquenched by the slow addition of ice. (Here I let it stir over theweekend—but not necessary). The organic layer was separated and theaqueous layer was extracted with CHCl₃ (2×100 mL). The combined organiclayer was washed with NaHCO₃ (1×150 mL), H_(2O ()1×150 mL), NaHSO₃(1×150 mL), H₂O (1×150 mL), brine (1×150 mL) and dried over MgSO₄. Theresidue was recrystallized from EtOH to afford the desired product,16.12 g (67%). An additional 1.87 g was obtained by columnchromatography of the concentrated filtrate (SiO₂, 5% ethylacetate-hexane). Total yield 17.99g (74%).

[0255] 2-Bromo-6-chloro-4-(trifluoromethyl)quinolinamine (5):2-Bromo-6-chloro-3-nitro-4-(trifluoromethyl)-quinoline (4, 4.5 g, 12.7mmol) was suspended in AcOH (120 mL). Fe powder (3.5 g, 63.3 mmol) wasadded and the reaction was stirred under N₂ at 60° C. for 2 h. The AcOHwas removed by rotary evaporation and the residue was partitionedbetween EtOAc (100 mL) and H₂O (100 mL). The biphasic mixture wassonicated for 30 s and then filtered through celite. The organic phasewas washed with H₂O (1×75 mL), 1N aq. NaOH soln. (1×75 mL), H₂O (1×75mL) and brine (1×50 mL), then dried over MgSO₄. Silica Chromatography(SiO₂, 65 mm×13 cm, 10% EtOAc-hexane) provided 5 as an off-whitecrystalline solid (2.30 g, 56%). mp 118° C. R_(f) 0.4 (10% Ethylacetate-hexane). ¹H NMR (CDCl₃, 300 MHz) δ7.90 (m, 1H), 7.85 (d, J=8.8Hz, 1H), 7.44 (dd, J=2.2, 8.7 Hz, 1H), 5.37 (br s, 2H, NH₂); ¹⁹F NMR(CDCl₃, 300 MHz) δ-54.5; ¹³C NMR (CDCl₃, 75 MHz) δ139.42, 136.87,136.72, 135.20, 130.60, 127.26, 126.78, 125.47, 123.13, 121.87, 121.81;IR (KBr) υ_(max) 3550, 3412, 1615, 1604, 1339, 1302, 1211, 1148, 1120,1097, 1037, 974, 818 cm⁻¹.

[0256] Anal. Calcd for C₁₀H₅BrClF₃N₂: C, 36.90; H, 1.55; N, 8.61. Found:C, 37.10; H, 1.86; N, 8.46.

[0257] 2-Bromo-6-chloro-4-(trifluoromethyl)quinolinecarbonitrile (6):2-Bromo-6-chloro-4-(trifluoromethyl)-quinolineamine (5, 476 mg, 1.46mmol) was dissolved in anhydrous DMF (5 mL) under N₂. Zn(CN)₂ (103 mg,0.88 mmol) was added and the solution was degassed with a stream of N₂.Pd(PPh₃)₄ (34 mg, 0.029 mmol) was added and the solution was degassedagain and then heated to 140° C. The reaction was complete by TLC after80 min. The reaction mixture was cooled to rt and diluted with EtOAc(100 mL), The organic phase was washed with H₂O (2×20 mL) and brine(1×20 mL) then dried over MgSO₄. Concentration and chromatography (SiO₂,40 g, 10% EtOAc-hexane) provided the desired material 6 as a yellowcrystalline solid (202 mg, 51%). mp 188° C. R_(f) 0.34 (10% Ethylacetate-hexane). ¹H NMR (CDCl₃, 300 MHz) δ7.95 (d, J=8.8 Hz, 1H), 7.94(m, 1H), 7.52 (dd, J=2.2, 8.8 Hz, 1H), 5.34 (br s, 2H, NH₂); ¹⁹F NMR(CDCl₃, 300 MHz) δ-54.51; ¹³C NMR (CDCl₃, 75 MHz) δ140.21, 139.00,138.39, 132.27, 128.25, 126.65, 126.10, 122.98, 121.90, 121.84, 114.43;IR (KBr) υ_(max) 3485, 3410, 3386, 2230, 1650, 1639, 1574, 1492, 1430,1352, 1322, 1221, 1158, 1130, 1121, 1095, 975, 822 cm⁻¹.

[0258] Anal. Calcd for C₁₁H₅ClF₃N₃: C, 48.64; H, 1.86; N, 15.47. Found:C, 48.71; H, 1.77; N, 15.27.

[0259] Alternatively, the above reaction can be run at 110° C., for 5-6h to give 15.6 g, 95% yield.

[0260] 8-Chloro-10-(trifluoromethyl)pyrimido[5,4-b]quinolin-4(3H)-one(7): 2-Bromo-6-chloro-4-(trifluoromethyl)-quinolinecarbonitrile (6, 150mg, 0.552 mmol) was suspended in formic acid (1.8 mL). Sulfuric acid (2drops) was added and the reddish suspension was heated to 100° C. After2h, no starting material remained by TLC. The reaction was cooled to˜60° C. and diluted with H₂O. The precipitate was collected, washed withH₂O and air-dried to provide 7 as a pale yellow solid (140.5 mg, 85%)requiring no further purification. ¹H NMR (d₆-DMSO, 300 MHz) δ12.8 (brs, NH), 8.39 (d, J=9.1 Hz, 1 H), 8.33 (m, 1H), 8.31 (s, 1H), 8.01 (dd,J=2.2, 9.1 Hz, 1H); ¹⁹F NMR (CDCl₃, 300 MHz) δ-51.35.

[0261]10-Butyl-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(8): 8-Chloro-10-(trifluoromethyl)pyrimido[5,4-b]quinolin-4(3H)-one (7,87 mg, 0.290 mmol) was suspended in anhydrous THF-TMEDA (10:1, 2 mL) andcooled to −78° C. under a nitrogen atmosphere. n-BuLi (1.6M 0.73 mL, 4equiv) was added dropwise over 10 minutes. After the addition wascomplete, the reaction was stirred for 20 minutes at −78° C. and thenwarmed to rt over 45 minutes. The reaction was quenched with sat. NH₄Clsolution and then partitioned between H₂O and EtOAc. The aqueous layerwas extracted with EtOAc (2×) and Et₂O (2×). The combined organic phaseswere dried over Na₂SO₄ and concentrated. Chromatography (SiO₂, 50%EtOAc-hexane) afforded the desired material 8 as a tan solid (35.4 mg,34%). R_(f) 0.34 (50% Ethyl acetate-hexane). ¹H NMR (CDCl₃, 300 MHz)δ11.42 (br s, NH), 7.78 (s, 1H), 7.30 (m, 1H), 7.18 (dd, J=2.2, 8.5 Hz,1H), 6.95 (br s, NH), 6.77 (d, J=8.5 Hz, 1H), 2.75 (m, 1H); 2.12 (m,1H), 1.28 (m, 2H), .0.95 (m, 2H), 0.79 (t, J=7.4 Hz, 3H). ESI-HRMS358.0935 (M⁺+H, C₁₆H₁₅ClON₃F₃ requires 358.0934).

EXAMPLE 2

[0262]10-Butyl-8-cyano-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(9):10-Butyl-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(8, 34 mg, 0.095 mmol) was dissolved in NMP (0.5 mL, 0.2M). Zn (7.4 mg,0.114 mmol, 1.2 equiv), Zn(CN)₂ (6.7 mg, 0.057 mmol, 0.6 equiv) and2-(di-t-butylphosphino)biphenyl (23 mg, 0.076 mmol, 0.8 equiv) wereadded and the solution was degassed with a stream of nitrogen. Pd₂(dba)₃(17 mg, 0.019 mmol, 0.2 equiv) was added and the reaction was degassed asecond time before heating to 150° C. After 16 hours, the reaction wascomplete by TLC. The reaction was cooled to rt and diluted with EtOAc(0.7 mL). The organic phase was washed with 2N aq. NH₄OH solution, brineand then concentrated with a stream of N₂. Chromatography (SiO₂, 15%acetone-CH₂Cl₂, then 50% EtOAc-hexane) provided the desired material asa beige solid (8.7 mg, 26%). R_(f) 0.27 (50% Ethyl acetate-hexane). ¹HNMR (CDCl₃, 300 MHz) 610.53 (br s, NH), 7.87 (s, 1H), 7.69 (s, 1H), 7.54(d, J=8.5 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 2.86 (m, 1H), 1.39 (m, 2H),0.99 (m, 2H), 0.86 (t, J=7.3 Hz, 3H). ¹⁹F NMR (CDCl₃, 300 MHz) δ-75.62;ESI-HRMS 349.1295 (M⁺+H, C₁₇H₁₅F₃N₄O requires 349.1276).

EXAMPLE 3

[0263]

[0264]8-Chloro-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(10): Tri-n-butyl-isopropoxymethyl-stannane (19 mL, 47.2 mmol) wasdissolved in anhydrous THF (50 mL) under N₂ and cooled to −78° C. n-BuLi(1.6 M in THF, 29.5 mL, 47.2 mmol) was added and the reaction mixturewas stirred for 15 min before the addition of ZnCl₂ (0.5 M in THF, 47.2mL, 23.6 mmol). The reaction was allowed to warm slowly to rt and wasstirred for 2 h. The zinc mixture was transferred via cannula to asolution of8-Chloro-10-(trifluoromethyl)pyrimido[5,4-b]quinolin-4(3H)-one (7, 2.47g, 7.87 mmol) in THF (100 mL). The reaction mixture was stirredovernight at room temperature. After quenching with sat. aq. NH₄Cl, thereaction mixture was partitioned between EtOAc and H₂O. The organicphase was washed with H₂O (1×), dried over Na₂SO₄, and concentrated.Chromatography (SiO₂, 50% EtOAc-hexane) afforded the desired material asa white solid (696 mg, 24%). R_(f) 0.35 (50% Ethyl acetate-hexane). ¹HNMR (d₆-acetone, 300 MHz) δ11.47 (br s, NH), 8.30 (br s, NH), 7.88 (s,1H), 7.35 (d, J=8.7 Hz, 1H), 7.27 (dd, J=2.3, 8.7 Hz, 1H), 4.68 (d,J=9.0 Hz, 1H), 4.34 (d, J=9.0 Hz, 1H), 3.66 (m, 1H), 1.03 (d, J=6.1 Hz,1H), 0.97 (d, J=6.1 Hz, 1H); ¹⁹F NMR (d₆-acetone, 300 MHz) δ-73.83;ESI-HRMS 374.0905(M⁺+H, C₁₆H₁₅ClF₃N₃O₂ requires 374.0883).

EXAMPLE 4

[0265]8-Cyano-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(11):8-Chloro-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(10, 696 mg, 1.86 mmol) was dissolved in anhydrous NMP (15 mL). Znpowder (268 mg, 4.10 mmol) and Zn(CN)₂ (437 mg, 3.72 mmol) were addedand the reaction mixture was degassed under vacuum (3×).Pd(dppf)Cl₂.CH₂Cl₂ (1.67 g, 2.05 mmol) was added and the reaction wasdegassed again under vacuum (3×). After heating to 170° C. for 16 hours,the reaction was cooled to rt and partitioned between EtOAc and 1N NH₄OHsolution. The biphasic mixture was filtered through celite and theaqueous phase was removed. The organic phase was washed with H₂O (2×),dried over MgSO4 and concentrated. The dark brown oil was redissolved inNMP (15 mL) and subjected to the identical reaction conditions for asecond time. After workup, the dark brown oil was obtained. Flashchromatography (SiO₂, 50% EtOAc-hexane) followed by PTLC (30%Acetone-hexane) afforded the desired material as a yellow solid (80 mg,12%). R_(f) 0.29 (50% Ethyl acetate-hexane). ¹H NMR (d₆-acetone, 300MHz) δ11.62 (br s, NH), 8.76 (br s, NH), 7.97 (s, 1H), 7.96 (s, 1H),7.62 (dd, J=1.9, 8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 4.72 (d, J=9.0 Hz,1H), 4.41 (d, J=9.0 Hz, 1H), 3.68 (m, 1H), 1.03 (d, J=6.1 Hz, 3H), 0.98(d, J=6.1 Hz, 3H); ¹⁹F NMR (d₆-acetone, 300 MHz) δ-74.11; ESI-HRMS365.1223 (M⁺+H, C₁₇H₁₅F₃N₄O requires 365.1225).

[0266]8-Cyano-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(11) was separated into enantiomers by chiral HPLC.

EXAMPLE 5

[0267]

[0268] 3-Amino-6-chloro-4-(trifluoromethyl)-2-quinolinecarboxamide (12):10-Butyl-8-cyano-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(9, 264 mg, 0.972 mmol) was dissolved in CH₃OH-CH₂Cl₂ (1:2, 6.5 mL) andtreated with tetrabutylammonium hydrogen sulfate (109 mg, 0.321 mmol)and 30% aq. H₂O₂ (1.98 mL). The reaction was cooled to 0° C. and 5N aq.NaOH solution (5.8 mL) was added. After the addition was complete, thereaction mixture had solidified. Additional CH₃OH—CH₂Cl₂ (6 mL) wasadded to dissolve the solids. The reaction was allow to warm to rt andstir overnight. The reaction mixture was partitioned between EtOAc (25mL) and H₂O (25 mL), and the aqueous layer was extracted with EtOAc(3×15 mL). The combined organic phases were washed with brine, dried(MgSO₄) and concetrated. Chromatography (SiO₂, 40 g, 30% EtOAc-hexane)afforded the desired product as a yellow crystalline solid (183 mg,65%). mp 200° C. R_(f) 0.37 (10% EtOAc-hexane). ¹H NMR (CDCl₃, 300 MHz)δ8.20 (br s, NH₂), 7.91 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.40 (dd,J=2.2, 9.0 Hz, 1H), 5.63 (br s, NH₂); ¹⁹F NMR (CDCl₃, 300 MHz) δ-54.42;¹³C NMR (CDCl₃, 75 MHz) δ168.75, 141.64, 137.05, 136.90, 135.87, 131.96,128.07, 126.59, 123.84, 121.45, 121.38; IR (KBr) υ_(max) 3515, 3447,3268, 3204, 1690, 1674, 1597, 1586, 1438, 1357, 1315, 1303, 1226, 1109,974, 822, 750 cm⁻¹.

[0269] Anal. Calcd for C₁₁H₇ClF₃N₃O: C, 45.62 H, 2.44; N, 14.51. Found:C, 45.73; H, 2.34; N, 14.18.

[0270]8-Chloro-2-methyl-10-(trifluoromethyl)-pyrimido[5,4-b]quinolin-4(3H)-one(13): 3-Amino-6-chloro-4-(trifluoromethyl)-2-quinolinecarboxamide (12,172 mg, 0.594 mmol) was dissolved acetylacetone (5.9 mL). Three drops ofH₂SO₄ were added and the reaction was heated to 100° C. for 30 minutes.The reaction was cooled to rt and the copious cream precipitate wascollected and washed with cold CH₃OH to provide the desired product (103mg, 55%) requiring no further purification. ¹H NMR (d₆-DMSO, 300 MHz)δ12.73 (br s, NH), 8.35 (d, J=9.2 Hz, 1 H), 8.29 (s, 1H), 7.97 (dd,J=2.2, 9.1 Hz, 1H), 2.44 (s, 3H); ¹⁹F NMR (CDCl₃, 300 MHz) δ-51.34; IR(KBr) υ_(max) 3442, 3060, 2920, 1706, 1629, 1608, 1560, 1485, 1336,1329, 1198, 1144, 1114, 961, 837, 710 cm⁻¹.

[0271]10-Butyl-8-chloro-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(14):8-Chloro-2-methyl-10-(trifluoromethyl)-pyrimido[5,4-b]quinolin-4(3H)-one(13, 82 mg, 0.261 mmol) was suspended in THF-TMEDA (10:1, 1.74 mL) andcooled to −78° C. under a N₂ atmosphere. n-BuLi was added dropwise andthe reaction slowly became homogeneous. The reaction mixture was stirredat −78° C. for 20 minutes, then the ice bath was removed and thereaction allowed to warm to rt. After stirring for 90 min, the reactionwas quenched with sat. aq. NH₄Cl and was partitioned between EtOAc andH₂O. The organic layer was separated and the aqueous layer was extractedwith EtOAc (3×10 mL). The combined organics were washed with brine,dried over Na₂SO₄ and concentrated. Chromatography (SiO₂, 60%EtOAc-hexane) provided the desired material 14 (17 mg, 17%). R_(f) 0.39(50% EtOAc-hexane). ¹H NMR (CDCl₃, 300 MHz) 6 11.63 (br s, NH), 7.53 (s,1H), 7.22 (dd, J=2.2, 8.4 Hz, 1H), 6.87 (br s, NH), 6.82 (d, J=8.4 Hz,1H), 2.86 (m, 1H), 2.48 (s, 3H), 2.14 (m, 1H), 1.34 (m, 2H), 1.01 (m,2H), 0.86 (t, J=7.3 Hz, 3H); ¹⁹F NMR (CDCl₃, 300 MHz) δ-75.21. ESI-HRMS372.1099 (M⁺+H, C₁₇H₁₇ClON₃F₃ requires 372.1091).

EXAMPLE 6

[0272]8-Chloro-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(15): Tri-n-butyl-isopropoxymethyl-stannane (0.774 mL, 1.92 mmol) wasdissolved in anhydrous THF (2 mL) under N₂ and cooled to −78° C. n-BuLi(1.6 M in THF, 1.2 mL, 1.92 mmol) was added and the reaction mixture wasstirred for 15 min before the addition of ZnCl₂ (0.5 M in THF, 1.92 mL,0.96 mmol). The reaction was allowed to warm slowly to rt and wasstirred for 90 min. The zinc mixture was transferred via cannula to asolution of8-Chloro-2-methyl-10-(trifluoromethyl)pyrimido[5,4-b]quinolin-4(3H)-one(13, 99 mg, 0.32 mmol) in THF (4 mL). The reaction mixture was stirredovernight at room temperature. After quenching with sat. aq. NH₄Cl, thereaction mixture was partitioned between EtOAc and H₂O. The organicphase was washed with H₂O (1×), dried over Na₂SO₄, and concentrated.Chromatography (PTLC, SiO₂, 50% EtOAc-hexane) afforded the desiredmaterial as a white solid (25 mg, 20%). R_(f) 0.37 (50% EtOAc-hexane).¹H NMR (acetone-d₆, 300 MHz) δ11.15 (br s, NH), 8.23 (s, 1H), 7.55 (s,1H), 7.31 (d, J=8.7 Hz, 1H), 7.24 (dd, J=2.2, 8.7 Hz, 1H), 4.71 (d,J=8.9 Hz, 1H), 4.31 (d, J=8.9 Hz, 1H), 2.86 (m, 1H), 3.66 (m, 1H), 2.38(s, 3H), 1.02 (d, J=6.1 Hz, 3H), 0.99 (d, J=6.1 Hz, 3H); ¹⁹F NMR(acetone-d₆, 300 MHz) δ-73.73. ESI HRMS m/z 388.1040 (M⁺+H,C₁₇H₁₇ClF₃N₃O₂ requires 388.1040)

EXAMPLE 7

[0273]8-Cyano-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(16):8-Chloro-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(15, 4.45 g, 11.47 mmol) was dissolved in anhydrous NMP (70 mL). Znpowder (900 mg, 13.76 mmol) and Zn(CN)₂ (2.69 g, 22.94 mmol) were addedand the reaction mixture was degassed under vacuum (3×). [(t-Bu)₃P]₂ Pd(4.79 g, 9.18 mmol) was added and the reaction was degassed again undervacuum (3X). After heating to 170° C. for 16 hours, the reaction wascooled to rt and most of the NMP was removed by vacuum distillation at60° C. The cooled residue was diluted with EtOAc and filtered throughcelite to provide a yellow oil. Flash chromatography (SiO₂, 10%Acetone-CH₂Cl₂) provided an oil which was partiioned between EtOAc andH₂O. The organic layer was washed with H₂O (1×) to removed any residualNMP, dried over MgSO₄ and concentrated. Trituration of the resultingsolid with CH₂Cl₂ provided the desired material as a white powder (3.56g, 82%). mp 277.3-278.1° C. (decomp). R_(f) 0.21 (50% EtOAc-hexane). ¹HNMR (acetone-PH-7410 NP 300 MHz) δ11.51 (br s, NH), 8.59 (s, 1H), 7.95(s, 1H), 7.59 (dd, J=1.8, 8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.74 (d,J=9.0 Hz, 1H), 4.38 (d, J=9.0 Hz, 1H), 3.68 (m, 1H), 2.40 (s, 3H), 1.02(d, J=5.9 Hz, 3H), 0.99 (d, J=6.2 Hz, 3H); ¹⁹F NMR (acetone-d₆, 300 MHz)δ-74.04; ¹³C NMR (acetone-d₆, 75 MHz) δ205.3, 156.4, 148.8, 142.7,134.5, 132.2, 130.2, 127.6, 125.2, 123.8, 119.0, 116.3, 115.4, 103.1,72.5, 64.5, 21.3, 21.1, 20.5; IR (KBr) υ_(max) 3426, 2973, 2883, 2222,1676, 1612, 1506, 1372, 1323, 1247, 1231, 1178, 1127, 1113, 1041, 987,881, 837, 752 cm⁻¹. ESI HRMS m/z 379.1387 (M⁺+H, C₁₈H₁₈F₃N₄O₂ requires379.1382).

EXAMPLE 8

[0274]8-Chloro-10-(2-cyclopropylethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(17): To a stirred solution of 1-cyclopropyl-2-iodoethane (12.5g, 63.9mmol, 5 equiv) in anhydrous Et₂O (128 mL) at −78° C. was addedtert-butyl lithium (1.7M in pentane, 75 mL, 128 mmol, 10 equiv). Theresulting white suspension was stirred at −78° C. for 50 min and addedvia cannula to a suspension of 7 (3.83 g, 12.8 mmol) in THF (64 mL) at−78° C. The resulting dark yellow mixture was stirred at −78° C. for 30min and then allowed to warm to 0° C. over 5 h. The reaction wasquenched with satd. NH₄Cl (100 mL) and H₂O (100 mL). The reactionmixture was extracted with EtOAc (3×100 mL) and the combined organiclayers washed with brine and dried (MgSO₄). Chromatography (SiO₂, 40 to50% EtOAc-hexane) provided the desired product as a yellow solid (2.92g, 62%). ESI HRMS m/z 370.1735 (M⁺+H, C₁₇H₁₆ClF3N30 requires 370.0934).

EXAMPLE 9

[0275]8-Cyano-10-(2-cyclopropylethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(18): A mixture of 17 (110 mg, 0.297 mmol), Zn(CN)₂ (71 mg, 0.594 mmol,2 equiv), [(t-Bu)₃P]₂ Pd (0.78 g, 0.149 mmol, 0.5 equiv) and Zn powder(29 mg, 0.446 mmol, 1.5 eq) were suspended in anhydrous NMP anddegassed. The reaction mixture was heated to 170° C. for 30 h. Aftercooling to 25° C., the reaction was quenched with 2 N NH₄OH (20 mL) andextracted with EtOAc (2×25 mL). The combined organic phases were washedwith brine, dried (MgSO₄) and concentrated. Chromatography (SiO₂, 50 to60% EtOAc-hexane) afforded the desired product as an off-white solid (49mg, 46%). mp >280° C. ESI HRMS m/z 361.1293 (M⁺+H, C₁₈H₁₆F₃N₄O requires361.1276).

EXAMPLE 10

[0276]10-(4-Bromobenzyl)-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one(19): To a stirred suspension of 7 (200 mg, 0.667 mmol) in THF (4 mL) at−40° C. was added 4-bromobenzyl magnesium bromide (0.25 M in Et₂O, 13.3mL, 3.34 mmol). The reaction was warmed slowly to 0° C. over 2 h. Afterstirring an additional 2 h, the reaction was quenched with H₂O (20 mL)and extracted with EtOAc (2×20 mL). The combined organic layers werewashed with brine, dried (MgSO₄) and concentrated. Chromatography (SiO₂,40 to 50% EtOAc-hexane) afforded the desired product as a viscous orangeoil (134 mg, 43%). ESI-MS m/z 470.2 (M⁺+H, C₁₉H₁₂BrClF₃N₃O).

[0277] The following compounds have been made using the techniquesdescribed above. TABLE 1*

Ex Mass MP # R^(a) R² R^(3a) Spec (° C.) 1 H n-butyl Cl 358.0935 2 Hn-butyl CN 349.1295 3 H i-propoxymethyl Cl 374.0905 4 H i-propoxymethylCN 365.1223   4a H i-propoxymethyl CN (R-configuration)  4b Hi-propoxymethyl CN (S-configuration) 5 CH₃ n-butyl Cl 372.1099 6 CH₃i-propoxymethyl Cl 388.1040 7 CH₃ i-propoxymethyl CN 379.1387 8 H2-cyclopropylethyl Cl 370.1735 9 H 2-cyclopropylethyl CN 361.1293 10  H4-bromobenzyl Cl 470.2

[0278] The following table contains representative examples of thepresent invention. Each entry in each table is intended to be pairedwith the formula at the start of the table. For example, in Table 2, thecompound is intended to be paired with one of 1a-11a, one of 1b-4b, oneof 1c-4c, one of 1d-5d and one of 1-60e. TABLE 2

# R¹  1a CF₃  2a CHF₂  3a CH₃  4a cyclopropyl  5a CF₂CF₃  6a methyl  7aethyl  8a propyl  9a butyl 10a CN 11a hydroxymethyl # R^(3a)  1b H  2bchloro  3b fluoro  4b CH₃  5b CN # R^(a)  1c chloro  2c methyl  3c H #R²  1e (6-methylpyrid-2-yl)methyl  2e Cyclopropylacetylenyl  3e n-Propyl 4e n-Butyl  5e 4-Fluorophenylmethyl  6e 2-Pyridylmethyl  7e i-Propyl 8e 3-Pyridylmethyl  9e 4-Pyridylmethyl 10e 3-Propynyl 11e2-Pyridylethynyl 12e 2-(2-Pyridyl)ethyl 13e n-Propyl 14e 3-Propenyl 15e2-Cyclopropylethyl 16e Ethynyl 17e 2-Ethoxyethyl 18e 2-chloroethyl 19eN-Cyclopropylaminomethyl 20e Hydroxymethyl 21e n-Propoxymethyl 22ei-Propoxymethyl 23e Methoxyethyl 24e diisopropoxymethyl 25ePropylaminomethyl 26e N-Methyl-i-propylaminomethyl 27en-Propylaminomethyl 28e Cyclobutylaminomethyl 29e i-Butylaminomethyl 30ecyclopropylthiomethyl 31e i-propylsulfoxymethyl 32e t-butylsulfoxymethyl33e methylthiomethyl 34e ethylthiomethyl 35e i-propylthiomethyl 36ecyclopropylmethoxymethyl 37e cyclobutoxymethyl 38e cyanomethyl 39e2-(ethylamino)ethyl 40e 2-(dimethylamino)ethyl 41e 2-(methylamino)ethyl42e 2-(i-propylamino)ethyl 43e 2-(cyclopropylamino)ethyl 44e pentyl 45evinyl 46e imidazolylethyl 47e pyrazolylethyl 48e 1,2,4-triazolylethyl49e 2-(methylethylamino)ethyl 50e 2-(i-propylethylamino)ethyl 51e2-(pyrrolidinyl)ethyl 52e 3-pentanylaminomethyl 53e dimethoxymethyl 54ei-butylaminomethyl 55e cyclopropylmethyl aminomethyl 56eallylaminomethyl 57e (R)-sec-butylaminomethyl 58e(S)-sec-butylaminomethyl 59e 1,3-dioxolanylmethyl 60e 1,3-dioxanylmethyl

UTILITY

[0279] The compounds of this invention possess reverse transcriptaseinhibitory activity and HIV inhibitory efficacy. The compounds offormula (I) possess HIV reverse transcriptase inhibitory activity andare therefore useful as antiviral agents for the treatment of HIVinfection and associated diseases. The compounds of formula (I) possessHIV reverse transcriptase inhibitory activity and are effective asinhibitors of HIV growth. The ability of the compounds of the presentinvention to inhibit viral growth or infectivity is demonstrated instandard assay of viral growth or infectivity, for example, using theassay described below.

[0280] The compounds of formula (I) of the present invention are alsouseful for the inhibition of HIV in an ex vivo sample containing HIV orexpected to be exposed to HIV. Thus, the compounds of the presentinvention may be used to inhibit HIV present in a body fluid sample (forexample, a serum or semen sample) that contains or is suspected tocontain or be exposed to HIV.

[0281] The compounds provided by this invention are also useful asstandard or reference compounds for use in tests or assays fordetermining the ability of an agent to inhibit viral replication and/orHIV reverse transcriptase, for example in a pharmaceutical researchprogram. Thus, the compounds of the present invention may be used as acontrol or reference compound in such assays and as a quality controlstandard. The compounds of the present invention may be provided in acommercial kit or container for use as such standard or referencecompound.

[0282] Since the compounds of the present invention exhibit specificityfor HIV reverse transcriptase, the compounds of the present inventionmay also be useful as diagnostic reagents in diagnostic assays for thedetection of HIV reverse transcriptase. Thus, inhibition of the reversetranscriptase activity in an assay (such as the assays described herein)by a compound of the present invention would be indicative of thepresence of HIV reverse transcriptase and HIV virus.

[0283] As used herein “μg” denotes microgram, “mg” denotes milligram,“g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar and “nm” denotes nanometer.“Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

[0284] Compounds tested in the assay described below are considered tobe active if they exhibit a K_(i) of ≦10 μM. Other compounds of thepresent invention have K_(i)'s of ≦1 μM. Other compounds of the presentinvention have K_(i)'s of ≦0.1 μM. Other compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Other compounds of the presentinvention have K_(i)'s of ≦0.001 μM.

[0285] Using the methodology described below, a number of compounds ofthe present invention were found to exhibit a K_(i) of ≦10 μM, therebyconfirming the utility of the compounds of the present invention aseffective HIV reverse transcriptase inhibitors.

HIV RNA Assay

[0286] DNA Plasmids and in Vitro RNA Transcripts:

[0287] Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp113-1816) cloned into PTZ 19R was prepared according toErickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5,577. The plasmid was linearized with Bam HI prior to the generation ofin vitro RNA transcripts using the Riboprobe Gemini system II kit(Promega) with T7 RNA polymerase. Synthesized RNA was purified bytreatment with RNase free DNAse (Promega), phenol-chloroform extraction,and ethanol precipitation. RNA transcripts were dissolved in water, andstored at −70° C. The concentration of RNA was determined from the A₂₆₀.

[0288] Probes:

[0289] Biotinylated capture probes were purified by HPLC after synthesison an Applied Biosystems (Foster City, Calif.) DNA synthesizer byaddition of biotin to the 5′ terminal end of the oligonucleotide, usingthe biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30,6287. The gag biotinylated capture probe (as described in WO01/29037,published Apr. 26, 2001) was complementary to nucleotides 889-912 ofHXB2 and the pol biotinylated capture probe (see WO01/29037) wascomplementary to nucleotides 2374-2395 of HXB2. Alkaline phosphataseconjugated oligonucleotides used as reporter probes were prepared bySyngene (San Diego, Calif.). The pol reporter probe (see WO01/29037) wascomplementary to nucleotides 2403-2425 of HXB2. The gag reporter probe(see WO01/29037) was complementary to nucleotides 950-973 of HXB2. Allnucleotide positions are those of the GenBank Genetic Sequence Data Bankas accessed through the Genetics Computer Group Sequence AnalysisSoftware Package (Devereau Nucleic Acids Research 1984, 12, 387). Thereporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl,0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. Thebiotinylated capture probes were prepared as 100 μM stocks in water.

[0290] Streptavidin Coated Plates:

[0291] Streptavidin coated plates were obtained from DuPontBiotechnology Systems (Boston, Mass.).

[0292] Cells and Virus Stocks:

[0293] MT-2 and MT-4 cells were maintained in RPMI 1640 supplementedwith 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells,2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF waspropagated in MT-4 cells in the same medium. Virus stocks were preparedapproximately 10 days after acute infection of MT-4 cells and stored asaliquots at −70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells(see below). Each aliquot of virus stock used for infection was thawedonly once.

[0294] For evaluation of antiviral efficacy, cells to be infected weresubcultured one day prior to infection. On the day of infection, cellswere resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulkinfections or at 2×10⁶/mL in Dulbecco's modified Eagles medium with 5%FCS for infection in microtiter plates. Virus was added and culturecontinued for 3 days at 37° C.

[0295] HIV RNA Assay:

[0296] Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5M GED and capture probe to a final guanidinium isothiocyanateconcentration of 3 M and a final biotin oligonucleotide concentration of30 nM. Hybridization was carried out in sealed U bottom 96 well tissueculture plates (Nunc or Costar) for 16-20 hours at 37° C. RNAhybridization reactions were diluted three-fold with deionized water toa final guanidinium isothiocyanate concentration of 1 M and aliquots(150 μL) were transferred to streptavidin coated microtiter plateswells. Binding of capture probe and capture probe-RNA hybrid to theimmobilized streptavidin was allowed to proceed for 2 hours at roomtemperature, after which the plates were washed 6 times with DuPontELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20)A second hybridization of reporter probe to the immobilized complex ofcapture probe and hybridized target RNA was carried out in the washedstreptavidin coated well by addition of 120 μl of a hybridizationcocktail containing 4×SSC, 0.66% Triton×100, 6.66% deionized formamide,1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at37° C., the plate was again washed 6 times. Immobilized alkalinephosphatase activity was detected by addition of 100 μL of 0.2 mM4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer (2.5 Mdiethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetatedihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). Theplates were incubated at 37° C. Fluorescence at 450 nM was measuredusing a microplate fluorometer (Dynateck) exciting at 365 nM.

[0297] Microplate Based Compound Evaluation in HIV-1 Infected MT-2Cells:

[0298] Compounds to be evaluated were dissolved in DMSO and diluted inculture medium to twice the highest concentration to be tested and amaximum DMSO concentration of 2%. Further three-fold serial dilutions ofthe compound in culture medium were performed directly in U bottommicrotiter plates (Nunc). After compound dilution, MT-2 cells (50 μL)were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well).Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂incubator. For evaluation of antiviral potency, an appropriate dilutionof HIV-1 (RF) virus stock (50 μL) was added to culture wells containingcells and dilutions of the test compounds. The final volume in each wellwas 200 μL. Eight wells per plate were left uninfected with 50 μL ofmedium added in place of virus, while eight wells were infected in theabsence of any antiviral compound. For evaluation of compound toxicity,parallel plates were cultured without virus infection.

[0299] After 3 days of culture at 37° C. in a humidified chamber insidea CO₂ incubator, all but 25 μL of medium/well was removed from the HIVinfected plates. Thirty seven μL of 5 M GED containing biotinylatedcapture probe was added to the settled cells and remaining medium ineach well to a final concentration of 3 M GED and 30 nM capture probe.Hybridization of the capture probe to HIV RNA in the cell lysate wascarried out in the same microplate well used for virus culture bysealing the plate with a plate sealer (Costar), and incubating for 16-20hrs in a 37° C. incubator. Distilled water was then added to each wellto dilute the hybridization reaction three-fold and 150 μL of thisdiluted mixture was transferred to a streptavidin coated microtiterplate. HIV RNA was quantitated as described above. A standard curve,prepared by adding known amounts of pDAB 72 in vitro RNA transcript towells containing lysed uninfected cells, was run on each microtiterplate in order to determine the amount of viral RNA made during theinfection.

[0300] In order to standardize the virus inoculum used in the evaluationof compounds for antiviral activity, dilutions of virus were selectedwhich resulted in an IC₉₀ value (concentration of compound required toreduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL.IC₉₀ values of other antiviral compounds, both more and less potent thanddC, were reproducible using several stocks of HIV-1 (RF) when thisprocedure was followed. This concentration of virus corresponded to˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well andtypically produced approximately 75% of the maximum viral RNA levelachievable at any virus inoculum. For the HIV RNA assay, IC₉₀ valueswere determined from the percent reduction of net signal (signal frominfected cell samples minus signal from uninfected cell samples) in theRNA assay relative to the net signal from infected, untreated cells onthe same culture plate (average of eight wells). Valid performance ofindividual infection and RNA assay tests was judged according to threecriteria. It was required that the virus infection should result in anRNA assay signal equal to or greater than the signal generated from 2 ngof pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in eachassay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateaulevel of viral RNA produced by an effective reverse transcriptaseinhibitor should be less than 10% of the level achieved in anuninhibited infection. A compound was considered active if its IC₉₀ wasfound to be less than 20 μM.

[0301] For antiviral potency tests, all manipulations in microtiterplates, following the initial addition of 2×concentrated compoundsolution to a single row of wells, were performed using a PerkinElmer/Cetus ProPette.

Protein Binding and Mutant Resistance

[0302] In order to characterize NNRTI compounds for their clinicalefficacy potential the effect of plasma proteins on antiviral potencyand measurements of antiviral potency against wild type and mutantvariants of HIV that carry amino acid changes in the known binding sitefor NNRTIs were examined. The rationale for this testing strategy is twofold:

[0303] 1. Many drugs are extensively bound to plasma proteins. Althoughthe binding affinity for most drugs for the major components of humanplasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein(AAG), is low, these major components are present in high concentrationin the blood. Only free or unbound drug is available to cross theinfected cell membrane for interaction with the target site (i.e., HIV-1reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAGon the antiviral potency in tissue culture more closely reflects thepotency of a given compound in the clinical setting. The concentrationof compound required for 90% inhibition of virus replication as measuredin a sensitive viral RNA-based detection method is designated the IC90.The fold increase in apparent IC90 for test compounds in the presence oradded levels of HSA and AAG that reflect in vivo concentrations (45mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the foldincrease, the more compound will be available to interact with thetarget site.

[0304] 2. The combination of the high rate of virus replication in theinfected individual and the poor fidelity of the viral RT results in theproduction of a quasi-species or mixtures of HIV species in the infectedindividual. These species will include a majority wild type species, butalso mutant variants of HIV and the proportion of a given mutant willreflect its relative fitness and replication rate. Because mutantvariants including mutants with changes in the amino acid sequence ofthe viral RT likely pre-exist in the infected individual'squasi-species, the overall potency observed in the clinical setting willreflect the ability of a drug to inhibit not only wild type HIV-1, butmutant variants as well. We thus have constructed, in a known geneticbackground, mutant variants of HIV-1 that carry amino acid substitutionsat positions thought to be involved in NNRTI binding, and measured theability of test compounds to inhibit replication of these mutantviruses. The concentration of compound required for 90% inhibition ofvirus replication as measured in a sensitive viral RNA-based detectionmethod is designated the IC90. It is desirable to have a compound whichhas high activity against a variety of mutants.

Dosage and Formulation

[0305] The antiviral compounds of this invention can be administered astreatment for viral infections by any means that produces contact of theactive agent with the agent's site of action, i.e., the viral reversetranscriptase, in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butpreferably are administered with a pharmaceutical carrier selected onthe basis of the chosen route of administration and standardpharmaceutical practice.

[0306] The dosage administered will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration; the age,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;and the effect desired. A daily dosage of active ingredient can beexpected to be about 0.001 to about 1000 milligrams per kilogram of bodyweight, with the preferred dose being about 0.1 to about 30 mg/kg.

[0307] Dosage forms of compositions suitable for administration containfrom about 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

[0308] Gelatin capsules contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

[0309] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts, and sodium EDTA. In addition, parenteral solutions cancontain preservatives, such as benzalkonium chloride, methyl- orpropyl-paraben and chlorobutanol. Suitable pharmaceutical carriers aredescribed in Remington's Pharmaceutical Sciences, supra, a standardreference text in this field.

[0310] Useful pharmaceutical dosage-forms for administration of thecompounds of this invention can be illustrated as follows:

[0311] Capsules

[0312] A capsule formulation of the present invention can be prepared byfilling standard two-piece hard gelatin capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6mg magnesium stearic.

[0313] Soft Gelatin Capsules

[0314] A soft gelatin capsule formulation of the present invention canbe prepared as follows. A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil can be prepared andinjected by means of a positive displacement pump into gelatin to formsoft gelatin capsules containing 100 mg of the active ingredient. Thecapsules should then be washed and dried.

[0315] Tablets

[0316] A tablet formulation of the present invention can be prepared byconventional procedures so that the dosage unit is 100 mg of activeingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 mg of microcrystalline cellulose, 11 mg ofstarch and 98.8 mg of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

[0317] Suspension

[0318] An aqueous suspension formulation can be prepared for oraladministration so that each 5 mL contain 25 mg of finely divided activeingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodiumbenzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

[0319] Injectable

[0320] A parenteral formulation suitable for administration by injectioncan be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution is sterilized bycommonly used techniques.

Combination Administration of Therapeutic Agents

[0321] The present invention provides a method for the treatment of HIVinfection which comprises administering, in combination, to a host inneed thereof a therapeutically effective amount of the following:

[0322] (a) a compound of formula (I); and

[0323] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors and HIV protease inhibitors, in oneor more sterile containers.

[0324] Each therapeutic agent component of this combination method(i.e., component (a) and (b) set forth above) can independently beadministered in any separate dosage form, such as those described above,and can be administered in various ways, as described above. In thefollowing description component (b) is to be understood to represent oneor more agents as described previously. Each individual therapeuticagent comprising component (b) may also be independently be administeredin any separate dosage form, such as those described above, and can beadministered in various ways, as described above.

[0325] Components (a) and any one or more of the agents comprisingcomponent (b) of the combination method of the present invention may beformulated together, in a single dosage unit (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.) as a combinationproduct. When component (a) and (b) are not formulated together in asingle dosage unit, the component (a) may be administered at the sametime as component (b) or in any order; for example component (a) of thisinvention may be administered first, followed by administration ofcomponent (b), or they may be administered in the revserse order. Ifcomponent (b) contains more that one agent, e.g., one RT inhibitor andone protease inhibitor, these agents may be administered together or inany order. When not administered at the same time, preferably theadministration of component (a) and (b) occurs less than about one hourapart. Preferably, the route of administration of component (a) and (b)is oral. The terms oral agent, oral inhibitor, oral compound, or thelike, as used herein, denote compounds which may be orally administered.Although it is preferable that component (a) and component (b) both beadministered by the same route (that is, for example, both orally) ordosage form, if desired, they may each be administered by differentroutes or dosage forms (for example, one component of the combinationmethod may be administered orally, and another component may beadministered intravenously).

[0326] As is appreciated by a medical practitioner skilled in the art,the dosage of the combination therapy of the invention may varydepending upon various factors such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration, the age, health and weight of the recipient, the natureand extent of the symptoms, the kind of concurrent treatment, thefrequency of treatment, and the effect desired, as described above.

[0327] The proper dosage of components (a) and (b) of the combinationmethod of this invention will be readily ascertainable by a medicalpractitioner skilled in the art, based upon the present disclosure. Byway of general guidance, typically a daily dosage may be about 100milligrams to about 1.5 grams of each component. If component (b)represents more than one compound, then typically a daily dosage may beabout 100 milligrams to about 1.5 grams of each agent of component (b).By way of general guidance, when the compounds of component (a) andcomponent (b) are administered in combination, the dosage amount of eachcomponent may be reduced by about 70-80% relative to the usual dosage ofthe component when it is administered alone as a single agent for thetreatment of HIV infection, in view of the synergistic effect of thecombination.

[0328] The combination products of this invention may be formulated suchthat, although the active ingredients are combined in a single dosageunit, the physical contact between the active ingredients is minimized.In order to minimize contact, for example, where the product is orallyadministered, one active ingredient may be enteric coated. By entericcoating one of the active ingredients, it is possible not only tominimize the contact between the combined active ingredients, but also,it is possible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low-viscosity grade ofhydroxypropyl methylcellulose or other appropriate materials as known inthe art, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component. In each formulation wherein contact is preventedbetween components (a) and (b) via a coating or some other material,contact may also be prevented between the individual agents of component(b).

[0329] Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

[0330] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time or concurrently by the same manner, will be readilyapparent to those skilled in the art, based on the present disclosure.

[0331] Pharmaceutical kits useful for the treatment of HIV infection,which comprise a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of component (a) and one or morecompounds of component (b), in one or more sterile containers, are alsowithin the ambit of the present invention. Sterilization of thecontainer may be carried out using conventional sterilizationmethodology well known to those skilled in the art. Component (a) andcomponent (b) may be in the same sterile container or in separatesterile containers. The sterile containers of materials may compriseseparate containers, or one or more multi-part containers, as desired.Component (a) and component (b) may be separate, or physically combinedinto a single dosage form or unit as described above. Such kits mayfurther include, if desired, one or more of various conventionalpharmaceutical kit components, such as for example, one or morepharmaceutically acceptable carriers, additional vials for mixing thecomponents, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, may also be included in thekit.

[0332] As will be appreciated by one of skill in the art, numerousmodifications and variations of the present invention are possible inlight of the above teachings. It is therefore to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise than as specifically described herein.

What is claimed is:
 1. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or apharmaceutically acceptable salt form thereof, wherein: A is a ringselected from:

P is O or S; Q is O or NH; R^(a) is selected from H, CN, C₁₋₄ alkyl,C₁₋₄ alkenyl, C₁₋₄ alkynyl, OH, C₁₋₄ alkyl-O—, C₁₋₄ alkyl-NH—, and NH₂;R^(b) is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, and C₁₋₄ alkynyl; Wis N or CR³; X is N or CR^(3a); Y is N or CR^(3b); Z is N or CR^(3c);provided that if two of W, X, Y, and Z are N, then the remaining areother than N; R¹ is selected from the group cyclopropyl, hydroxymethyl,CN, and C₁₋₄ alkyl substituted with 0-9 halogen; R² is selected from thegroup methyl substituted with 0-3 R^(3f), C₁₋₆ alkyl substituted with0-2 R⁴, C₂₋₆ haloalkyl, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2R^(3d), phenyl substituted with 0-2 R^(3d), and 3-6 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-2 R^(3d); R³ is selected from the groupH, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, CF₃, F, Cl, Br, I,—(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —(CH₂)_(t)NHC(O)R⁷,—(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —S—C₁₋₄alkyl, —S(O)C₁₋₄alkyl,—S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ringcontaining 1-4 heteroatoms selected from the group O, N, and S; R^(3a)is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, CF₃,F, Cl, Br, I, —(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—(CH₂)_(t)NHC(O)R⁷, —(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —S—C₁₋₄alkyl,—S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S; alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3d)is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl,Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a),—NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3a) and R^(3b) togetherform —OCH₂O—; R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3b)and R^(3c) together form —OCH₂O—; R^(3d), at each occurrence, isindependently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy,OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3e), at eachoccurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH,C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3f), ateach occurrence, is independently selected from the group H, F, Cl, Br,I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, OCF₃, —O(CO)—R¹³, —OS(O)₂C₁₋₄alkyl,—NR¹²R^(12a), —C(O)R¹³, —NHC(O)R¹³, —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—NHSO₂R¹⁰, and —SO₂NR¹²R^(12a); R⁴ is selected from the group H, F, Cl,Br, I, C₁₋₆ alkyl substituted with 0-2 R^(3e), C₃₋₁₀ carbocyclesubstituted with 0-2 R^(3e), phenyl substituted with 0-5 R^(3e), and a5-10 membered heterocyclic system containing 1-3 heteroatoms selectedfrom the group O, N, and S, substituted with 0-2 R^(3e); R⁵ and R^(5a)are independently selected from the group H and C₁₋₄ alkyl;alternatively, R⁵ and R^(5a), together with the nitrogen to which theyare attached, combine to form a 5-6 membered ring containing 0-1 O or Natoms; R⁶ is selected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, andNR⁵R^(5a); R⁷ is selected from the group H, C₁₋₃ alkyl and C₁₋₃ alkoxy;R⁸ is selected from the group H, (C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy,(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀aryl)methylcarbonyl, (C₁₋₄ alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀arylcarbonyloxy(C₁₋₄ alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆alkyl)carbonyl; R⁹ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, (C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀aryloxy, (C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ arylcarbonyloxy(C₁₋₄alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl,phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆ alkyl)carbonyl; R¹⁰ isselected from the group C₁₋₄ alkyl and phenyl; R¹¹ is selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted with C₃₋₆cycloalkylsubstituted with 0-2 R^(3e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocyclesubstituted with 0-2 R^(3e); R¹² and R^(12a) are independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₆cycloalkylsubstituted with 0-2 R^(3e), and C₃₋₆ carbocycle substituted with 0-2R^(3e); alternatively, R¹² and R^(12a) can join to form 4-7 memberedheterocyclic ring; R¹³ is selected from the group H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —O—C₂₋₆ alkenyl,—O—C₂₋₆ alkynyl, NR¹²R^(12a), C₃₋₆carbocycle, and —O—C₃₋₆carbocycle; andt is selected from 0 and
 1. 2. A compound of claim 1 or pharmaceuticallyacceptable salt forms thereof, wherein: R² is selected from the groupmethyl substituted with 0-3 R^(3f), C₁₋₅ alkyl substituted with 0-2 R⁴,C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d), and phenyl substitutedwith 0-2 R^(3d), and 3-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-2R^(3d), wherein the heterocyclic system is selected from 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R³ and R^(3a), at eachoccurrence, are independently selected from the group H, C₁₋₄ alkyl, OH,C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷,NHC(O)NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4heteroatoms selected from the group O, N, and S; alternatively, R³ andR^(3a) together form —OCH₂O—; R^(3b) and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F,Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);alternatively, R^(3a) and R^(3b) together form —OCH₂O—; R⁴ is selectedfrom the group H, Cl, F, C₁₋₄ alkyl substituted with 0-2 R^(3e), C₃₋₆carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-5R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-2R^(3e); R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅; R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅,and NR⁵R^(5a); and R⁷ is selected from the group CH₃, C₂H₅, CH(CH₃)₂,OCH₃, OC₂H₅, and OCH(CH₃)₂.
 3. A compound of claim 2, wherein: P is O;Ring A is:

R^(a), at each occurrence, is selected from H, C₁₋₄ alkyl, C₁₋₄alkyl-NH—, NH₂; R^(c) is selected from H and methyl; W is CR³; X isCR^(3a); Y is CR^(3b); Z is CR^(3c); R² is selected from the groupmethyl substituted with 0-3 R^(3f), C₁₋₃ alkyl substituted with 0-2 R⁴,C₂₋₃ alkenyl substituted with 0-2 R⁴, C₂₋₃ alkynyl substituted with 0-1R⁴, and C₃₋₆ cycloalkyl substituted with 0-2 R^(3d); R³, R^(3a), R^(3b),and R^(3c), at each occurrence, are independently selected from thegroup H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN,C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a); alternatively, R³ and R^(3a)together form —OCH₂O—; R^(3e), at each occurrence, is independentlyselected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl,—NR⁵R^(5a), —C(O)R⁶, and —SO₂NR⁵R^(5a); R^(3f), at each occurrence, isindependently selected from the group H, F, Cl, Br, I, C₁₋₄ alkyl, CN,—OH, —O—R¹¹, , —O(CO)—R¹³, —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, and —NR¹²R^(12a);R⁴ is selected from the group H, Cl, F, C₁₋₄ alkyl substituted with 0-1R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substitutedwith 0-2 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R⁵ and R^(5a) areindependently selected from the group H, CH₃ and C₂H₅; R⁶ is selectedfrom the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a); R⁷ isselected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; R⁸ is H; R⁹ is H,methyl, ethyl, propyl, and i-propyl; R¹¹ is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocyclesubstituted with 0-2 R^(3e) wherein the C₃₋₆ carbocycle is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl; and R¹² andR^(12a) are independently selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocycle substituted with0-2 R^(3e) wherein the C₃₋₆ carbocycle is selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and phenyl.
 4. A compound of claim3, or a pharmaceutically acceptable salt form thereof, wherein: R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₃ alkylsubstituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴, and C₂₋₃alkynyl substituted with 1 R⁴; R³, R^(3a), R^(3b), and R^(3c), at eachoccurrence, are independently selected from the group H, C₁₋₃ alkyl, OH,C₁₋₃ alkoxy, F, Cl, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, andNHC(O)NR⁵R^(5a); alternatively, R³ and R^(3a) together form —OCH₂O—;R^(3e), at each occurrence, is independently selected from the groupCH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a); R^(3f), at each occurrence,is independently selected from the group H, F, Cl, Br, I, C₁₋₄ alkyl,—OH, CN, —O—R¹¹, —O(CO)—R¹³, and —NR¹²R^(12a), —SR¹¹, —S(O)R¹¹,S(O)₂R¹¹, and —OS(O)₂methyl; R⁴ is selected from the group H, Cl, F,CH₃, CH₂CH₃, cyclopropyl substituted with 0-1 R^(3e),1-methyl-cyclopropyl substituted with 0-1 R^(3e), cyclobutyl substitutedwith 0-1 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-1 R^(3e), wherein the heterocyclicsystem is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl,2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R⁵and R^(5a) are independently selected from the group H, CH₃ and C₂H₅; R⁶is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and R⁹ isselected from H and methyl.
 5. A compound of claim 4, or apharmaceutically acceptable salt form thereof, wherein: R² is selectedfrom the group methyl substituted with 0-2 R^(3f), methyl substitutedwith 0-2 R⁴, ethyl substituted with 0-2 R⁴, propyl substituted with 0-2R⁴, ethenyl substituted with 0-2 R⁴, 1-propenyl substituted with 0-2 R⁴,2-propenyl substituted with 0-2 R⁴, ethynyl substituted with 0-2 R⁴,1-propynyl substituted with 0-2 R⁴, 2-propynyl substituted with 0-2 R⁴,and cyclopropyl substituted with 0-1 R^(3d); R^(3e), at each occurrence,is independently selected from the group CH₃, —OH, OCH₃, OCF₃, F, Cl,and —NR⁵R^(5a); R⁴ is selected from the group H, Cl, F, CH₃, CH₂CH₃,cyclopropyl substituted with 0-1 R^(3e), 1-methyl-cyclopropylsubstituted with 0-1 R^(3e), cyclobutyl substituted with 0-1 R^(3e),phenyl substituted with 0-2 R^(3e), and a 5-6 membered heterocyclicsystem containing 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-1 R^(3e), wherein the heterocyclic system is selectedfrom the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl R⁵ and R^(5a) areindependently selected from the group H, CH₃ and C₂H₅; R⁶ is selectedfrom the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a); R⁷ isselected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; R⁸ is H.
 6. Acompound of claim 5, or a pharmaceutically acceptable salt form thereof,wherein: R¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,cyclopropyl, CF₃, CF₂CH₃, CN, and hydroxymethyl; R² is selected from thegroup methyl substituted with 0-2 R^(3f), methyl substituted with 0-2R⁴, ethyl substituted with 0-2 R⁴, propyl substituted with 0-1 R⁴,ethenyl substituted with 0-2 R⁴, 1-propenyl substituted with 0-2 R⁴,2-propenyl substituted with 0-2 R⁴, ethynyl substituted with 0-2 R⁴,1-propynyl substituted with 0-2 R⁴; R³, R^(3b), and R^(3c) are H; R^(3e)is CH₃; R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —NR¹²R^(12a); R⁴ is selected from the group H,cyclopropyl substituted with 0-1 R^(3e), and a 5-6 membered heterocyclicsystem containing 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-1 R^(3e), wherein the heterocyclic system is selectedfrom the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R¹² and R^(12a) areindependently selected from H, methyl, ethyl, propyl, and i-propyl, andC₃₋₆ carbocycle substituted with 0-2 R^(3e) wherein the C₃₋₆ carbocycleis selected from cyclopropyl.
 7. A compound of claim 5, or apharmaceutically acceptable salt form thereof, wherein: ring A is

R^(a) is H, methyl, ethyl, propyl, and i-propyl; R¹ is CF₃; R² isselected from methyl substituted with 0-1 R^(3f), ethyl, propyl,i-propyl, and butyl; W is CH; X is CR^(3a); Y is CH; Z is CH; R^(3a) isselected from H, F, Cl, Br, and CN; R^(3f) is —O—R¹¹; R⁸ is H; and R¹¹is selected from methyl, ethyl, propyl, i-propyl, butyl, s-butyl,i-butyl, and t-butyl.
 8. A compound of claim 1, or a pharmaceuticallyacceptable salt form thereof, wherein the compound is of formula (Ic):


9. A compound of claim 1, or a pharmaceutically acceptable salt formthereof, wherein the compound of formula (I) is selected from:10-Butyl-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;10-Butyl-8-cyano-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;8-Chloro-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;8-Cyano-10-(isopropoxymethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;10-Butyl-8-chloro-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;8-Chloro-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;8-Cyano-10-(isopropoxymethyl)-2-methyl-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;8-Chloro-10-(2-cyclopropylethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;8-Cyano-10-(2-cyclopropylethyl)-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one;and10-(4-Bromobenzyl)-8-chloro-10-(trifluoromethyl)-5,10-dihydropyrimido[5,4-b]quinolin-4(3H)-one.10. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording claim 1 or pharmaceutically acceptable salt form thereof. 11.A method for treating HIV infection which comprises administering to ahost in need of such treatment a therapeutically effective amount of acompound according to claim 1 or pharmaceutically acceptable salt formthereof.
 12. A method of treating HIV infection which comprisesadministering, in combination, to a host in need thereof atherapeutically effective amount of: (a) a compound according to claim1; and, (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors, HIV protease inhibitors, fusioninhibitors, and CCR-5 inhibitors.
 13. A method of claim 12, wherein thereverse transcriptase inhibitor is selected from the group AZT, ddC,ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, trovirdine, MKC-442,HBY 097, HBY1293, GW867, ACT, UC-781, UC-782, RD4-2025, MEN 10979,AG1549 (S1153), TMC-120, TMC-125, Calanolide A, and PMPA, and theprotease inhibitor is selected from the group saquinavir, ritonavir,indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333,KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390,PD 178392, U-140690, ABT-378, DMP-450, AG-1776, VX-175, MK-944, andVX-478, the CCR-5 inhibitor is selected from TAK-779 (Takeda), SC-351125(SCH-C, Schering) and SCH-D (Schering), and the fusion inhibitor isselected from T-20 and T1249.
 14. A method of claim 13, wherein thereverse transcriptase inhibitor is selected from the group AZT,efavirenz, and 3TC and the protease inhibitor is selected from the groupsaquinavir, ritonavir, nelfinavir, and indinavir.
 15. A method of claim14, wherein the reverse transcriptase inhibitor is AZT.
 16. A method ofclaim 15, wherein the protease inhibitor is indinavir.
 17. Apharmaceutical kit useful for the treatment of HIV infection, whichcomprises a therapeutically effective amount of: (a) a compoundaccording to claim 1; and, (b) at least one compound selected from thegroup consisting of HIV reverse transcriptase inhibitors and HIVprotease inhibitors, in one or more sterile containers.